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The induction of hepatic cytochrome P-450-linked monooxygenases has been studied after the twice daily, oral administration of two imidazo[4,5-c]pyridine-containing compounds and one imidazo[4,5-b]pyridine-containing drug. The compounds were administered by the oral route, at different doses, for 6 days after which time hepatic microsomes were prepared. In vitro biochemical assays revealed that all three compounds increased the O-deethylation of 7-ethoxyresorufin in a dose-dependent manner while not significantly affecting either the O-dealkylation of 7-ethoxycoumarin or the levels of NADPH-cytochrome c reductase. Ethylmorphine N-demethylation was decreased after dosing with the imidazo[4,5-b]pyridine-containing drug. Levels of cytochrome(s) P-450 and liver-to-body weight ratios were not significantly altered. The imidazo[4,5-b]pyridine-containing compound was more potent in terms of the induction of 7-ethoxyresorufin than either of the imidazo[4,5-c]pyridine-containing compounds but was approximately fourfold less active in this regard than 3-methylcholanthrene. No induction of cytochrome-P-450-linked monooxygenase activities was evident at a twice daily dose of 5 mg/kg for 6 days for all three compounds tested, constituting a no-effect level. The imidazo[4,5-c]pyridine-containing compounds exhibited modified Type II difference spectra when added to a suspension of rat hepatic microsomes. The imidazo[4,5-b]pyridine-containing compound has previously been reported to be a rapid and potent inducer of monooxygenase activity and have a Type II difference spectrum.

Acute, subchronic, and chronic toxicity studies were conducted in dogs with the new vasodilator/cardiotonic drug isomazole (IMZ) to support, in part, clinical investigations of this agent in humans. Single oral doses of IMZ of 25, 50, or 100 mg/kg given to English pointer dogs (2/dose) caused a marked drop in systemic blood pressure and reflex-induced increases in heart rate to values well over 200 beats per minute. These responses were maintained for 12 to 22 hr depending on the dose given. One of the dogs receiving 100 mg/kg died at 4.5 hr postdose. Results of subchronic (3 months) and chronic (1 year) studies in beagle dogs (4/sex/dose group), in which measurable plasma levels of the drug and its metabolites were found, indicated that IMZ did not produce any discernible adverse findings when given in doses up to 16 mg/kg, other than expected cardiotoxic effects. The plasma t1/2 of IMZ at 16 mg/kg increased to between 4 and 8 hr from 2 hr noted at lower doses. In the 1-year study, at all doses and in both sexes, plasma levels of IMZ declined over the first month, stabilizing (at the 2 and 6 mg/kg doses) thereafter for the duration of the study. At the high dose of 16 mg/kg, after 1 year plasma levels of IMZ exceeded (females) or equaled (males) the 1-month values. At peak plasma levels of IMZ (2 hr postdose), plasma levels of parent drug increased linearly with the dose. The cardiotoxic effects consisted of substantial postdose increases in heart rate throughout the course of treatment (5 mg/kg and above), significant increases in heart weight (6 mg/kg and above), and multifocal myocardial fibrosis (6 mg/kg and above). There was a decline in basal heart rate at doses of 12.5 mg/kg and higher. The results of these studies demonstrated that repeated IMZ administration, as expected, was cardiotoxic to the dog, a species relatively sensitive to the pharmacological activity and hemodynamic changes induced by vasodilator/cardiotonic drugs. The no-effect dose level for cardiotoxicity in the repeated dose studies was considered to be 2 mg/kg, the lowest dose tested.

Acute, subchronic, and chronic toxicity studies were conducted with isomazole, a new (investigational) inotropic agent with significant vasodilator properties. When given acutely to either young adult rats or mice, the oral median lethal dose was approximately 135 or 525 mg/kg, respectively. Clinical signs of toxicity were leg weakness, hypoactivity, tremors, clonic convulsions, and ataxia. Fischer 344 rats (15/sex/group) were fed diets containing isomazole in concentrations of 0, 0.03, 0.1, or 0.3% for 3 months with no resulting mortality or clinical signs of toxicity. The average daily intake of the compound was approximately 0, 20, 65, or 198 mg/kg in both sexes. Body weight gain, food consumption, and efficiency of food utilization were significantly reduced only in males in the 198 mg/kg dose group. There were no changes of toxicological significance in any of the hematology, clinical chemistry, or urine parameters. Isomazole produced significant increases in hepatic p-nitroanisole O-demethylase activity and relative liver weight primarily at the 65 and 198 mg/kg treatment levels. These effects were consistent with induction of the hepatic drug-metabolizing enzyme system. Histopathologic findings consisted of centrilobular fat deposition in the livers of 9 of 15 males in the 198 mg/kg dose group, and periarteritis in the adventitia of small and medium-sized arteries in the mesentery in 3 of 30 and 12 of 30 animals from the 65 and 198 mg/kg dose groups, respectively. The plasma levels of isomazole had a tendency to drop after 90 days compared to Day 2 in all dose groups and was more apparent in male rats.(ABSTRACT TRUNCATED AT 250 WORDS)